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| Open AccessReply to: Does the KDEL receptor cycle between the Golgi and the ER?
- Jurgen Denecke
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Article
| Open AccessTANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry
How RNA polymerase II subunits enter the nucleus is not well understood. Here, the authors show that Transport and Golgi organization protein 6, TANGO6, recruits RNA polymerase II subunit B2, RPB2, to the ER membrane in a retrograde manner and transports it to the nucleus with the aid of importins.
- Zhi Feng
- , Shengnan Liu
- & Li Li
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Article
| Open AccesspiRNA loading triggers MIWI translocation from the intermitochondrial cement to chromatoid body during mouse spermatogenesis
piRNA processing factors and piRNA/PIWI complex are found in intermitochondrial cement (IMC) and chromatoid body (CB). Here, the authors show that piRNA loading orchestrates MIWI translocation from the IMC to CB, demonstrating its crucial role in spermatogenesis.
- Huan Wei
- , Jie Gao
- & Mo-Fang Liu
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Article
| Open AccessSimultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions
Protein function depends on their subcellular location and turnover rate. Here, the authors report a method to measure spatial and temporal proteome dynamics simultaneously, revealing compartment-specific protein turnover and translocation in cardiac cells under ER stress and carfilzomib treatment.
- Jordan Currie
- , Vyshnavi Manda
- & Edward Lau
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Article
| Open AccessA DARPin promotes faster onset of botulinum neurotoxin A1 action
Botulinum neurotoxins (BoNTs), the causative agents of the disease botulism, are potent biological toxins. Here the authors use Designed Ankyrin Repeat Proteins (DARPins) to probe BoNT structure and function: DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro was identified.
- Oneda Leka
- , Yufan Wu
- & Richard A. Kammerer
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Article
| Open AccessThe GET insertase exhibits conformational plasticity and induces membrane thinning
Tail-anchored (TA) membrane protein biogenesis is mediated by the GET insertase. Here, authors present cryo-EM and X-ray structures, MD simulations and functional data for human and fungal insertases showing membrane remodeling for TA insertion.
- Melanie A. McDowell
- , Michael Heimes
- & Irmgard Sinning
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Article
| Open AccessBile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling
Intestinal cholesterol is taken into endocytic recycling compartment via NPC1L1-mediated endocytosis. Here the authors show that certain bile acids facilitate cholesterol transport to the endoplasmic reticulum from endocytic recycling compartment in cells and NPC1L1 is then recycled back to the plasma membrane.
- Jian Xiao
- , Le-Wei Dong
- & Bao-Liang Song
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Article
| Open AccessExcessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P
Selenium and copper are two essential trace elements whose homeostasis and distribution is regulated by hepatic release of selenoprotein P (SELENOP) and ceruloplasmin, respectively. Here, the authors show that excessive copper results in hepatic SELENOP accumulation in the trans Golgi which might limit the selenium transport to peripheral organs.
- Maria Schwarz
- , Caroline E. Meyer
- & Anna P. Kipp
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Article
| Open AccessCharacterization of a fold in TANGO1 evolved from SH3 domains for the export of bulky cargos
The authors characterized a fold in the TANGO1 protein which evolved from SH3 domains for the export of bulky cargos such as collagen. They denote this fold as MOTH (MIA, Otoraplin, TALI/TANGO1 homology) domain.
- Oliver Arnolds
- & Raphael Stoll
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Article
| Open AccessStructural insight into the intraflagellar transport complex IFT-A and its assembly in the anterograde IFT train
IFT-A plays crucial roles in bidirectional ciliary transport, vital for cilia biogenesis and signaling. Here, Ma et al. report the IFT-A structure in two distinct states and unveil the assembly mechanism of IFT-A into the anterograde train.
- Yuanyuan Ma
- , Jun He
- & Ming Lei
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Article
| Open AccessOrthodenticle homeobox 2 is transported to lysosomes by nuclear budding vesicles
Many homeodomain transcription factors are secreted and move to neighboring cells. Here, orthodenticle homeobox 2 is shown to be exported from the nucleus in a nuclear membrane, which buds off to then be degraded or secreted.
- Jun Woo Park
- , Eun Jung Lee
- & Jin Woo Kim
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Article
| Open AccessBarrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length
The permeability barrier of the nuclear pore assembles from cohesive FG repeats. By systematic engineering and testing repeat variants, the authors pinpointed the sequence features that rule barrier assembly and transport selectivity.
- Sheung Chun Ng
- , Abin Biswas
- & Dirk Görlich
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Article
| Open AccessHedgehog is relayed through dynamic heparan sulfate interactions to shape its gradient
The Hedgehog morphogen creates gradients during development, but diffusion alone cannot explain its spatiotemporal dynamics. Hedgehog transport requires binding heparan sulfate sugar chains, and the authors now show that Hedgehogs can spread by interacting with sequential heparan molecules.
- Fabian Gude
- , Jurij Froese
- & Kay Grobe
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Article
| Open AccessThe mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase
The mitochondrial ATP synthase produces the bulk of cellular ATP. Here, the authors report a function of the mitochondrial Hsp70 in the formation of the catalytical head and in its assembly with the peripheral stalk to form the mature ATP synthase.
- Jiyao Song
- , Liesa Steidle
- & Thomas Becker
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Article
| Open AccessInterruption of post-Golgi STING trafficking activates tonic interferon signaling
Microbial DNA is recognized by the cGAS-STING pathway, which leads to a type I interferon response. Here authors show that a basal flux of interferon activation could also be triggered by interference with STING trafficking from the Golgi apparatus to the lysosomes.
- Xintao Tu
- , Ting-Ting Chu
- & Nan Yan
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Article
| Open AccessPromoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation
Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses
- Chengyu Shi
- , Ying Wang
- & Aifu Lin
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Article
| Open AccessDifferential nuclear import sets the timing of protein access to the embryonic genome
Here the authors address how embryos control the timing of specific gene activation in early frog development. They find transcription factors for early gene activation are maternally loaded and remain at constant levels, and rather that order of activation is based on their sequential entry into the nucleus based largely on their respective affinity to importins.
- Thao Nguyen
- , Eli J. Costa
- & Martin Wühr
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Article
| Open AccessProtein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy
Mitophagy activation is mediated by mitochondrial depolarization. Here, the authors show that mitochondrial protein misfolding can activate mitophagy in a depolarization-independent manner mediated by a protein import reduction.
- Jonas Benjamin Michaelis
- , Melinda Elaine Brunstein
- & Christian Münch
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Article
| Open AccessStomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth
Stomatin is a component of lipid rafts. Here, Wu et al. show that stomatin modulates the differentiation and functions of adipocytes by regulating adipogenesis signaling and fatty acid influx such that with excessive calorie intake, increased stomatin induces adiposity.
- Shao-Chin Wu
- , Yuan-Ming Lo
- & Chi-Hung Lin
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Article
| Open AccessDDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos
The DEAD box protein DDX1 is known to form large aggregates in the cytoplasm of early mouse embryos. Here the authors identify DDX1-containing vesicles and show that loss of Ddx1 affects their integrity, compromising mitochondria function and causing embryonic lethality.
- Yixiong Wang
- , Lubna Yasmin
- & Roseline Godbout
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Article
| Open AccessRibosome profiling reveals multiple roles of SecA in cotranslational protein export
Using a combination of ribosome profiling methods, Zhu et al. investigate the principles governing the cotranslational interaction of SecA with nascent proteins and reveal a hierarchical organization of protein export pathways in bacteria.
- Zikun Zhu
- , Shuai Wang
- & Shu-ou Shan
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Article
| Open AccessUBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony
Although ubiquitin ligases are known to control clock protein degradation, their other roles in clock neurons are unclear. Here the authors report that UBR4 promotes export of neuropeptides from the Golgi for axonal trafficking, which is important for circadian clock synchrony in mice and flies.
- Sara Hegazi
- , Arthur H. Cheng
- & Hai-Ying Mary Cheng
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Article
| Open AccessSirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43
TDP-43 is a nucleic acid binding protein, whose insoluble aggregates are neuropathological hallmarks of specific subsets of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Post-translational modifications and acetylation of TDP-43 impact its interaction with RNA, its localization in the cells, and are linked to disease. Using antibodies generated against TDP-43 lysine acetylation sites, sirtuin-1 was found to potently deacetylate amber suppressed [acK136]TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding as well as phase separation and aggregation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
- Jorge Garcia Morato
- , Friederike Hans
- & Philipp J. Kahle
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Article
| Open AccessMechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP
The translation of mechanical cues into gene expression changes is dependent on the nuclear import of mechanoresponsive transcriptional regulators. Here the authors identify that Importin-7 drives the nuclear import of one such regulator YAP while YAP then controls Importin-7 response to mechanical cues and restricts Importin-7 binding to other cargoes.
- María García-García
- , Sara Sánchez-Perales
- & Miguel A. Del Pozo
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Article
| Open AccessNuclear transporter Importin-13 plays a key role in the oxidative stress transcriptional response
Importin superfamily member IPO13 mediates nuclear transport bidirectionally. Here the authors delineate the transcriptome of wild-type and IPO13-knockout mouse embryonic stem cells, revealing IPO13’s key role in the oxidative stress response through targeted transport of specific transcription factors.
- K. A. Gajewska
- , H. Lescesen
- & D. A. Jans
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Article
| Open AccessATP-citrate lyase promotes axonal transport across species
Microtubule tracks are important for the transport of molecules within axons. Here, the authors show that ATAT1, the enzyme responsible for acetylating a-tubulin, receives acetyl groups from ATP citrate lyase whose stability is regulated by Elongator, a protein mutated in the neuronal disease Familial dysautonomia.
- Aviel Even
- , Giovanni Morelli
- & Laurent Nguyen
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Article
| Open AccessMapping protein interactions in the active TOM-TIM23 supercomplex
The TOM and TIM23 complexes facilitate the transport of nuclear-encoded proteins into the mitochondrial matrix. Here, the authors use a stalled client protein to purify the translocation supercomplex and gain insight into the TOM-TIM23 interface and the mechanism of protein handover from the TOM to the TIM23 complex.
- Ridhima Gomkale
- , Andreas Linden
- & Peter Rehling
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Article
| Open AccessNEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.
- Huibing Wang
- , Weiwei Qi
- & Junying Yuan
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Article
| Open AccessGlobal kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery
Mitochondrial protein import is mediated by the translocase of the outer membrane (TOM), through which nearly all precursors traverse. Here, the authors perform global in vitro kinome profiling and by this identify that DYRK1A phosphorylates TOM70 and promotes import.
- Corvin Walter
- , Adinarayana Marada
- & Chris Meisinger
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Article
| Open AccessRecapitulation of selective nuclear import and export with a perfectly repeated 12mer GLFG peptide
The permeability barrier of nuclear pore complexes blocks passage of inert macromolecules but allows rapid, receptor-mediated, and RanGTPase-driven transport of cargoes up to ribosome size. The authors now show that such a barrier can be faithfully recapitulated by an ultimately simplified FG phase assembled solely from a tandemly repeated 12mer GLFG peptide.
- Sheung Chun Ng
- , Thomas Güttler
- & Dirk Görlich
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Article
| Open AccessControl of membrane barrier during bacterial type-III protein secretion
Type-III secretion systems (T3SSs) are capable of translocating proteins with high speed while maintaining the membrane barrier for small molecules. Here, a structure-function analysis of the T3SS pore complex elucidates the precise mechanisms enabling the gating and the conformational changes required for protein substrate secretion.
- Svenja Hüsing
- , Manuel Halte
- & Thibaud T. Renault
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Article
| Open AccessUnravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay
Our understanding of cytosolic delivery is hindered by existing methods for quantification which suffer from being indirect and showing low sensitivity. Here the authors report a SLEEQ (Split Luciferase Endosomal Escape Quantification) assay to assess cytosolic delivery of cell-penetrating peptides.
- Serena L. Y. Teo
- , Joshua J. Rennick
- & Colin W. Pouton
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Article
| Open AccessThioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
Cold exposure activates thermogenesis and fatty acid oxidation in brown fat, a process suppressed by Them1. Here, the authors show that cold induces Them1 phosphorylation and loss of puncta that suppress fatty acid use, leading to a diffuse localization and increased energy expenditure in mice.
- Yue Li
- , Norihiro Imai
- & Susan J. Hagen
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Article
| Open AccessAnalysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system
Bacteria use the type 2 secretion system to secrete enzymes and toxins across the outer membrane to the environment. Here the authors analyse the T2SS pathway in three protist lineages and suggest that the early mitochondrion may have been capable of secreting proteins into the cytosol.
- Lenka Horváthová
- , Vojtěch Žárský
- & Pavel Doležal
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Article
| Open AccessDeletion of Mfsd2b impairs thrombotic functions of platelets
The mechanisms by which platelets release sphingosine-1-phosphate (S1P) is not well characterized. Here the authors show that Mfsd2b is required for S1P release from both resting and activated platelets and that deletion of Mfsd2b impairs thrombotic functions of platelets.
- Madhuvanthi Chandrakanthan
- , Toan Quoc Nguyen
- & Long N. Nguyen
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Article
| Open AccessMissense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
The R138Q mutation in the Fragile X Mental Retardation 1 (FMR1) gene has been associated with Fragile X syndrome (FXS). Here, the authors present a Fmr1R138Q Knock-In mouse model and show that R138Q mutation results in impaired long-term potentiation and socio-cognitive performance in these mice.
- Marta Prieto
- , Alessandra Folci
- & Stéphane Martin
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Article
| Open AccessLONP1 and mtHSP70 cooperate to promote mitochondrial protein folding
Most mitochondrial proteins are imported from the cytosol and must fold in the mitochondria. Here, the authors show that the mitochondrial protease LONP1 plays a critical role in the mtHSP70 chaperone system independently of its protease activity.
- Chun-Shik Shin
- , Shuxia Meng
- & David C. Chan
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Article
| Open AccessA ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex
Biochemistry combined with biophysical measurements and mathematical modeling offer insight into the mechanism by which the cotranslational chaperone, nascent polypeptide-associated complex (NAC), modulates substrate selection by signal recognition particle (SRP) and reduces aberrant, nonspecific targeting of ribosomes to the ER.
- Hao-Hsuan Hsieh
- , Jae Ho Lee
- & Shu-ou Shan
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Article
| Open AccessConcerted localization-resets precede YAP-dependent transcription
The transcriptional regulator YAP shuttles rapidly between the cytoplasm and nucleus, but whether and how dynamics such as amplitude and frequency affect target gene transcription is unclear. Here, using live imaging of endogenous YAP and target-gene transcription, the authors show that YAP-dependent signalling is encoded through rapid and concerted changes in the nucleo-cytoplasmic distribution of YAP.
- J. Matthew Franklin
- , Rajarshi P. Ghosh
- & Jan T. Liphardt
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Article
| Open AccessThe SecA motor generates mechanical force during protein translocation
The ATPase SecA drives Sec-dependent protein translocation across the bacterial plasma membrane. Here, the authors combine kinetic translocation measurements with single-molecule force spectroscopy and demonstrate that the SecA motor generates mechanical force to unfold and translocate preproteins.
- Riti Gupta
- , Dmitri Toptygin
- & Christian M. Kaiser
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Article
| Open AccessVesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster
Mitochondrial dynamics change during ageing, with larger mitochondria and altered protein import in older animals. Here the authors show that Dosmit protein mediates mitochondrial morphology with Rab32 by inducing double-membraned vesicles that regulate protein trafficking into mitochondria.
- Po-Lin Chen
- , Kai-Ting Huang
- & Chun-Hong Chen
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Article
| Open AccessPeroxisomal targeting of a protein phosphatase type 2C via mitochondrial transit
Import of proteins into specific cellular compartments is critical for organelle function and several proteins are known to be imported into multiple compartments. Here, the authors report that the protein Ptc5 is first sorted to and processed in the mitochondria before being targeted to peroxisomes, which may influence mitochondria-peroxisome interorganellar contact.
- Thorsten Stehlik
- , Marco Kremp
- & Johannes Freitag
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Article
| Open AccessTALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating
Most cells possess sensory cilia, which need to be gated properly. Here the authors show that the C. elegans proteins TALP-3 and ANKR-26 coordinate cilia gating in the context of transition fibers and that this mechanism is conserved in mammalian cells and likely implicated in certain ciliopathies.
- Hao Yan
- , Chuan Chen
- & Qing Wei
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Article
| Open AccessNucleoplasmic signals promote directed transmembrane protein import simultaneously via multiple channels of nuclear pores
The contribution of central and peripheral channels of nuclear pores to transport of transmembrane proteins is unclear. Here the authors show that most inner nuclear membrane proteins use only peripheral channels, but some extend nuclear localization signals into the central channel for directed nuclear transport.
- Krishna C. Mudumbi
- , Rafal Czapiewski
- & Weidong Yang
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Article
| Open AccessGrasp55−/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity
The physiological roles of the Golgi reassembly-stacking protein 55 (GRASP55/GORASP55) remain largely elusive. Here, the authors show that the Golgi-resident protein GRASP55 plays a crucial role in lipid homeostasis by regulating intestinal lipid uptake.
- Jiyoon Kim
- , Hyeyon Kim
- & Min Goo Lee
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Article
| Open AccessBrassinosteroid signaling delimits root gravitropism via sorting of the Arabidopsis PIN2 auxin transporter
Brassinosteroid signaling can regulate auxin transport by influencing the sorting and accumulation of PIN auxin efflux carriers. Here, the authors show that in roots, brassinolide can modulate vacuolar degradation and endocytic sorting of PIN2, delimiting root curvature in response to gravity.
- Katarzyna Retzer
- , Maria Akhmanova
- & Christian Luschnig
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Article
| Open AccessStructure of the substrate-engaged SecA-SecY protein translocation machine
Proteins are translocated across membranes through the Sec61/SecY channel. Here, the authors present the structure of a translocating peptide chain trapped inside the SecA-SecY complex which suggests how peptides are actively moved through the channel.
- Chengying Ma
- , Xiaofei Wu
- & Long Li
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Article
| Open AccessA TonB-dependent transporter is required for secretion of protease PopC across the bacterial outer membrane
TonB-dependent transporters (TBDTs) are outer membrane proteins that import nutrients and bacteriocins in bacteria. Here, Gómez-Santos et al. show that a TBDT is required for secretion of a protease in Myxococcus xanthus, suggesting that some TBDTs may be involved in protein secretion.
- Nuria Gómez-Santos
- , Timo Glatter
- & Lotte Søgaard-Andersen
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Article
| Open AccessRapid active zone remodeling consolidates presynaptic potentiation
Synaptic plasticity ensures functionality during perturbations and enables memory formation. Here, the authors describe homeostatic functional and nano-modular active zone modifications for immediate and long-lasting enhancement of neurotransmitter release, and identify Unc13 as a presynaptic molecular target for homeostatic potentiation and learning.
- Mathias A. Böhme
- , Anthony W. McCarthy
- & Alexander M. Walter